Meeting on Sentinel Surveillance for Drug Resistance in Leprosy

A Report 22-23 August 2011, Hyderabad, India

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Contents
Page 1. 2. 3. 4. 5. Background ....................................................................................................................................1 Objectives ......................................................................................................................................1 Opening session ............................................................................................................................. 1 Updates: 2010 surveillance activities............................................................................................. 2 Country presentation on relapse cases ........................................................................................... 3 5.1 5.2 5.3 5.4 5.5 6. Brazil ....................................................................................................................................3 China ..................................................................................................................................... 3 Madagascar ........................................................................................................................... 3 Mozambique ......................................................................................................................... 4 Nepal ..................................................................................................................................... 0

Technical discussion ...................................................................................................................... 0 6.1 6.2 High throughput routine drug resistance surveillance in leprosy: present and future technologies .......................................................................................................................... 0 Being prepared to detect for resistance to second line drugs: new fluroquinolones, clarithromycin and TMC207 ................................................................................................0

7.

Country presentation of drug resistance surveillance data............................................................. 0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 Brazil ....................................................................................................................................0 China ..................................................................................................................................... 0 Clumbia ................................................................................................................................0 India ......................................................................................................................................0 Mali....................................................................................................................................... 0 Myanmar ............................................................................................................................... 0 Nepal ..................................................................................................................................... 0 Philippine .............................................................................................................................. 0 Viet Nam............................................................................................................................... 0

7.10 Yemen ................................................................................................................................... 0 8. General discussion ......................................................................................................................... 0 8.1 8.2 8.3 9. Quality control: technology, logistics and reporting ............................................................ 0 Current developments in search for new anti-leprosy drugs ................................................ 0 Outcome of management of drugs resistant leprosy cases using second line drugs ............. 0
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Conclusion and recommendations ................................................................................................. 0

Annexes 1. 2. 3. Programme ..................................................................................................................................... 0 Participants ....................................................................................................................................0 Reference Laboratories collaborating with WHO Global Leprosy Programme for Sentinel Surveillance of Rifampicin Resistance ......................................................................0

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1.

Background

The fight against leprosy has been a great success largely due to the development of multidrug therapy (MDT) in 1981Resistance to dapsone has been reported since the late 1960s but convincing data supporting the existence of clofazimine resistant strains of M. leprae have not been reported. . Since rifampicin is the backbone of MDT, it is important to monitor the emergence of rifampicin-resistant mutants.

In addition, several new anti-mycobacterial drugs are either under development or are in the market against other infections. The emergence of drug resistance is a concern and a threat for many disease control programmes, especially when secondary prevention (chemotherapy) is the main component of the control strategy. To meet the challenge of containing the disease and to sustain the on-going declining trend of leprosy in endemic countries, it is essential to keep a vigil on drug sensitivity patterns in leprosy endemic communities.

2.

Objectives
to review the drug resistance surveillance data, to review trends in relapses reported by the national programmes, and to discuss recent advances in techniques for diagnosing drug resistance and in therapy for drug resistant cases.

The objectives of the meeting were:

3.

Opening session

Opening remarks were given by Dr V. M. Katoch, Director General, Indian Council of Medical Research (ICMR) and Dr Myo Thet Htoon, Team Leader, WHO Global Leprosy Programme. Professor Emmanuelle Cambau, Department of bacteriology and Hygiene, Faculty of Medicine, Paris, France was nominated as chairperson and Dr Vijayalakshmi Valluri from Blue Peter Public Health and Research Center, Hyderabad, India and Dr Khin Saw Aye, Immunology Research Division, Department of Medical Research (Lower Myanmar) were nominated as rapporteurs. A total of 40 participants including experts from the sentinel sites (Brazil, China, Colombia, India, Nepal, Mali, Madagascar, Myanmar, Philippines, Viet Nam and Yemen), researchers from the reference laboratories and partner organizations attended the meeting. The programme and list of participants are provided in Annex 1 and Annex 2 respectively.

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4.

Updates: 2010 surveillance activities

Dr Myo Thet Htoon updated the data about the surveillance system. In 2010-201, there were 14 participating countries: Burkina Faso, Madagascar, Mali and Mozambique for AFRO, Brazil and Columbia for AMRO, Pakistan and Yemen for EMRO, India, Myanmar and Nepal for SEARO and China, Philippines and Viet Nam for WPRO. In addition, 10 reference laboratories were involved. The current surveillance data are based on detecting drug resistant M. leprae in relapse cases of leprosy. Dr Myo Thet Htoon reminded the definition of a relapse cases which was decided at the previous meetings: (1) the re-occurrence of the disease at any time after completion of a full course with WHO recommended MDT with (2) the appearance of definite new skin lesions and/or an increase in the bacteriological index of 2 or more units at any single site compared to the same site at a previous examination. The procedure is to seek for missense mutations in the rpoB, folP and gyrA genes from a skin sample (skin smear or biopsy) from a lesion with a BI of 2+ or above. In 2010, reports were received from 8 countries (China, Columbia, India, Myanmar, Viet Nam, Pakistan, Philippines, and Yemen). A total of 109 MB relapse cases were reported: 80 with a bacteriological index (BI) of 2 and more and 75 cases with new skin lesions. There were no child cases reported and majority of relapses were among males (84%). Of these 109 relapse cases, 88 were tested for drug resistance. DNA amplification was reported to be negative for dapsone in 16 and for rifampcin in 17 cases (18%), which is much less that in 2009. Results of resistance associated with gene mutations were the following: 9 dapsone resistance cases and 1 rifampicin resistance. This results in 12.5% secondary resistance to dapsone (9/72 results of folP sequencing) and 1.4% secondary resistance to rifampicin (1/71results of rpoB sequencing). No mutation of the gyrA gene associated to ofloxacin resistance was reported. The definition of relapse was discussed, in order to increase the likelihood of including only true relapses and decrease the inclusion of cases of reversal reactions or those with high initial BI, who may remain smear-positive for some period after the completion of treatment with MDT.

5.

Country presentation on relapse cases

5.1 Brazil

The source of the data presented by Dr Philip Suffys, was SINAN National Information System of Communicable Diseases. Dr. Suffys mentioned that there were 1375 relapses reported during 2010. The male to female ratio among relapse cases was 1.82; majority of relapses were reported among MB cases (85%). Only about 1.4% were under the age of 15 years. The bacilloscopy results were available for 63.8% of the cases, of these 38.3% were positive and 25.5% were negative.

5.2

China

Dr Shen Jianping from the National Centre for Leprosy Control mentioned that China is detecting about 1500 new cases and about 150 relapses (after dapsone monotherapy and after MDT) are reported every year since 1986. During 2010, 1324 new cases were reported. The number of relapses reported for the year was 96 (61 after dapsone monotherapy and 35 after MDT). The number of relapses in 2010 is much smaller than previous years due to their efforts to improve the quality of relapse diagnosis and confirmation. Dr Jianping concluded by mentioning that WHOs recommendation of multidrug therapy regime is still effective for the treatment of leprosy. Thus, drug resistance in China may not be a serious problem.

5.3

Madagascar

Drug Surveillance data from Madagascar was presented by Dr Ramarolahy Emerantien Benoit. National Leprosy Programme was initiated in 1992 and leprosy elimination goal was reached by 2006. The WHO drug surveillance study was initiated in 2011. A stable new case detection and prevalence rate was observed from 2006 to 2010. In 2010, 1521 new cases were detected with 84% MB cases. In 2010, 8 relapse cases were reported and in the first half of 2011, 10 relapse cases were reported. Two relapse cases reported in 2011 were tested for drug resistance by applying molecular tools and were reported to be negative for PCR of rpoB, folP and gyrA genes. Both the cases were first diagnosed in 1977 and 1992 and reported as clinical relapse in 2011. Some of the problems mentioned were lack of capacity to collect sample at local level, delay in reporting from health centres and confusion between relapse and reaction. Future perspectives mentioned were establishing of sentinel sties in larger centres, training of local health staff on sampling techniques, improving clinical information of relapse at local level and improving early reporting of relapse cases.

5.3

Mozambique

Dr. Cyntaia Sema presented the data on Mozambique. Leprosy is an endemic disease in three provinces (Niassa, Cabo Delgado and Nampula) at the North of Mozambique. A decrease in prevalence was seen in three provinces from 2005 to 2010. Niassa province reported a decrease from 2.4 to 0.6; Cabo Delgado from 5.7 to 1.6 and Nampula reported a decrease in prevalence from 6.1 to 0.6. The National prevalence rate showed decrease from 2.5 in 2005 to 0.5 in 2010. New case detection rate showed a decrease from 24.8 to 6.5 in Niassa province, Cabo Delgado province showed a decrease in new cases from 2005 (57.8) to 2010 (17.7). In Nampula province there was a decrease in new case detection rate from 69.8 in 2005 to 7.2 in 2009 followed by a slight increase in new cases in 2010 (9). The national new case detection rate decreased from 27.7 in 2005 to 5.8 in 2010. Future perspective is to create and operate
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eight sentinel sites for the study of resistance to drugs used to treat leprosy throughout the country.

5.5

Nepal

General information about Nepal was presented by Dr. Mahesh Shah, Anandban Hospital, Kathmandu, which was followed by drug surveillance studies presented by Deanne Hagge the next day. New Case Detection rate decreased from 2008/2009 to 2010/2011 from 1.15 to 1.12. Proportion of child cases was reported as 5.19 in 2010/2011. There was an increase in Grad-2 deformity from 2.72 to 3.47 from 2009/10 to 2010/2011. Future perspectives include strengthening the referral centres; improve access of unreached groups, strengthening of new case detection activities and orientation programme on human rights for leprosy affected people.

6.
6.1

Technical discussion
High throughput routine drug resistance surveillance in leprosy: present and future technologies

Dr Varalakshmi Vissa presented the molecular tools she developed at the Department of Microbiology, Immunology and Pathology in Colorado State University. Each new or relapsed case is studied for genome strain typing by MVLA, SNPs detection or RFLP analysis, and detection of resistance associated mutations. Genome typing can show transmission of leprosy in a community. Detection of mutations was set through a real time PCR method using High Resolution Melt Curve assays (HRM) that permits to detect for targeted mutations without sequencing.

6.2 Being prepared to detect for resistance to second line drugs: new
fluoroquinolones, clarithromycin and TMC207 Dr Cambau presented the data on mechanisms of action and resistance for second line drugs such as clarithromycin, minocycline, moxifloxacin, ethionamide and the new TMC207 (ex. R207910). Other drugs in development are presented in another talk on the second day of the meeting. Some of these drugs are widely used for the treatment of common infectious such as respiratory and urinary tract infections. Consequently these antibiotics can select resistance mutants outside the treatment of leprosy. Similarly, ethionamide and TMC 207 will likely be used against tuberculosis. For all these drugs, the mechanisms of resistance are already known in other bacteria and mycobacteria although no drug resistant strain of M. leprae was described for clarithromycin, minocycline and TMC. Consequently the molecular tools will be ready if we need to detect for resistance: detection of mutations in rrs, rrl, atpe, gyrB and ethA genes to be added to the rpoB, gyrA and folP genes sequenced.

7. Country presentation on drug resistance surveillance data

7.1 Brazil

Dr Rosa Castlia Frana Ribeiro Soares presented the data on drug resistance surveillance carried out in Brazil. Total 132 relapse cases (116 MB and 16 PB) were diagnosed at seven sentinel sites in Brazil, of whom only 59 were recruited for surveillance. New skin lesions were reported in 49 cases and more than 2+ BI at any sites was reported in 39 cases. However, this number is only about 10% of total reported relapse in Brazil in 2010. Results of sequencing for drug resistance in leprosy is available from 40 relapse cases show no mutation in dapsone, rifampicin and ofloxacin controlling genes. Some experimental procedures were also presented. For patients sample collection, skin smears were taken from at least four sites and samples were washed within a sterile tube filled with 1 mL 70% ethanol. Specific pairs of primers were used for amplification of resistance genes to rifampicin (rpoB), dapsone (folP1) and ofloxacin (gyrA and results were reported according to the presence or absence of mutations. DNA aliquots of positive samples for drug resistance mutations and the same number with the absence of mutations were forwarded to FIOCRUZ/RJ Laboratory and other three reference labs in Brazil. 10% of all Brazilian samples were forwarded from FIOCRUZ to Dr. Masanori Matsuokas lab in Japan. For the cases for whom skin lesion biopsies are possible to be obtained in Reference Centres, samples were kept at 4C and shipped to the Microbiology Laboratory of the Instituto Lauro de Souza Lima, Bauru/SP, where the Shepard technique was performed for inoculating bacilli in mouse foot pad.

7.2

China

The data on surveillance carried out in China was presented by Dr Hongsheng Wang. About 1,300 new cases are detected in 2010. In addition, about 100 relapse cases were reported in 2010. The proportion of MB cases among all newly detected cases increased gradually during the past ten years. The classification of leprosy is followed WHO recommendation. MDT was implemented in whole China in 1986. Sample collections, transportation, storage, DNA extraction and PCR were performed according to the WHO guidelines. DNA sequencing was completed by Shanghai Sheng Gong Biology Company. A total of 10 patients were tested for the presence of drug resistant mutations. Among them, 6 were relapses after MDT, and 4 with persisting high BI after MDT. All samples were positive for PCR amplification of M.leprae DNA. Only one relapse patient displayed rpoB gene mutation.

7.3

Colombia

Dr Nora Cardona-Castro from the Instituto Colombiano de Medicina Tropical gave a presentation on the results of the surveillance data carried out during 2011. Drug resistance surveillance is not part of Leprosy Control Programme (LCP) activities. Dr Nora mentioned leprosy situation in Colombia, a total of 289 cases including 243 new cases and 46 relapses (22 PB and 24 MB) were reported in 2010. In 2011, 133 cases (110 new cases and 23 relapses) were detected. A high proportion of relapses is a major warning for the Colombian Leprosy Program but the causes of high reporting of relapses may be due to mis-diagnosis and mis-classification of patients (reactions). Resistance to rifampicin and dapsone are not seen in relapse cases in 2011 by mutation detection in E.Coli system. Group discussion suggested that for confirmation of detection of mutations for folP and rpoB in relapse cases must be sent to WHO recommended reference centre for further validation.
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7.4

India

Dr Rupendra Jadhav, Dr Vijayalakshmi, Dr Ram Das and Dr Krishnamurthy each presented the results of the drug resistance surveillance carried out by the Stanley Browne Laboratory in Delhi, Blue Peter Public Health & Research Centre (BPHRC) in Hyderabad, National JALMA Institute for Leprosy and Other Mycobacterial Diseases and Damien Foundation India Trust, India, repectively. Method of sample collection, transportation and testing from Stanley Browne Laboratory (SBL) in Delhi was as per the set guidelines provided to the TLM centres (slides were also sent to the lab), samples to be kept at room temperature / 4C and sent to S.B. Lab (SBL) for PCR and sequencing at a later date (preferably at the end of every month) by routine transport without the need to control the temperature during transportation, or to take additional precautions for biohazard control. A total of 21 MB relapse cases were diagnosed at the sentinel sites but only 13 of relapse cases were tested for drug resistance. None of the samples tested so far from relapse cases showed mutation for rifampicin resistance; therefore, MDT can be used for treating such patients. Blue Peter Public Health & Research Centre (BPHRC) in Hyderabad performed slit skin smear and kept in 70% Ethanol, DNA extraction was done by DNeasy Kit. Individual PCR for folp1, rpob, gyrA and sequencing were carried out at local laboratory. A total 30 relapse cases were diagnosed of whom only 17 cases were tested for sequencing. The results did not show mutations in folp1, rpoB and gyrA in any of the PCR positive samples. On behalf of National JALMA Institute for Leprosy and Other Mycobacterial Diseases (ICMR), Agra, Dr Ram Das presented results of 10 (BL/LL- 3 non-responder and 7 relapsed) cases. DNA was isolated and PCR-sequencing was performed for analysis of the mutation in folP1, rpoB and gyrA gene regions. Out of 10 samples, 7 got amplified and 3 samples could not be amplified due to low bacilli load. Seven amplified samples were sequenced for folP1, rpoB and gyrA gene. The sequencing results of 7 samples for folP1, rpoB and gyrA genes did not show any mutation. Dr Ram Das suggested that drug resistance in leprosy is very low in the MDT era. Further studies are needed with more non-responders and relapse cases for the detection of relevant mutations for deriving any meaningful conclusions. Dr Krishnamurthy from the Damien Foundation India Trust, India presented eleven leprosy projects offering primary and secondary services. All have laboratory facilities. All new cases are subjected to slit skin smear examination. In addition, three of the projects offer tertiary services and one of them is the sentinel centre for drug-resistance surveillance. Only one relapse case from among the cases managed by projects was investigated and drug susceptibility test showed no resistance.

7.5

Mali

Dr Roch Christian JOHNSON presented the surveillance activities that were carried out in Mali and Burkina Faso. Sampling within countries was performed according to the clinical case definition for relapse, punch biopsy specimens were sent by DHL to Paris to the laboratory of Professor Cambau. A total of 8 relapse cases were recruited in 2011, six cases from Mali and 2 cases from Burkina Faso. The results were negative PCR for rpoB, folP1 and
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gyrA genes for rifampicin, dapsone and ofloxacin from cases from Mali and no mutations of rpoB, folP1 and gyr A genes from cases of Burkina Faso. Dr Johnson gave suggestions to improve the quality of sampling and the diagnosis of relapse and expand surveillance network to others countries.

7.5

Myanmar

Dr Kyaw Kyaw presented the results of the surveillance activities that were carried out at two sentinel sites in Myanmar. These are Mandalay Special Clinic, Mandalay and Central special skin clinic, Yangon. A total of 12 relapse cases were recruited 7 cases from Yangon and Bago Divisions and 5 cases from Mandalay and Magwe Divisions. One to three skin smear samples were taken from each patient, kept without blade in 70% ethanol tubes and sent to reference laboratory of Leprosy Research Centre (LRC), National Institute of Infectious Diseases (NIID), Japan. Results of DNA sequencing for drugs resistance revealed no mutations in rpoB, folP1 and gyrA genes.

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7.5

Nepal

The data on leprosy surveillance carried out in Nepal was presented by Dr. Deanna A. Hagge, Head, Mycobacterial Research Laboratory, Anandaban Hospital, Kathmandu, Nepal. The centres inclusion into WHOs Global Surveillance of Drug Resistance in Leprosy was approved in October 2010 by the Government of Nepal and Nepal Health Research Council (NHRC).

Data were presented on results of biopsy from 5 relapse cases (4 Anandaban, 1 Lalgadh) in 2010 were explained, all are male MB patients with ages between 24 and 62 years. Relapses occurred between 5-28 years post-MDT. The average BI from SSS was 3.7 from four sites. All are histopathologically described as active BB-LL cases. Samples were sent to Stanley Browne Laboratory in New Delhi for sequencing and awaiting results.

7.7

Philippines

Surveillance for drug resistance in the Philippines was presented by Dr. Irene B. Mallari, representing the Leonard Wood Memorial Research Centre, which is the designated sentinel site. Two MB relapse cases were diagnosed and samples were sent to reference laboratory of National Hansens Disease Programs, Baton Rouge, Louisiana, USA for DNA sequencing. The results of both cases were sensitive to rifampicin, dapsone and ofloxacin.

7.8

Viet Nam

Dr. Nguyen Thi Hai Van gave a presentation on the results of the drug resistance surveillance carried out in Viet Nam. She presented leprosy situation in Viet Nam. In 2010 the detection rate is 0.41/100,000, prevalence rate is 0.04/10,000, MB proportion among new cases is 72.14%, children proportion among new cases is 3.9% and proportion of disability grade 2 among new cases is 18.66%. Five MB relapsed cases with BI>2+ were detected in 2011. All are male and age between 19 to 61 years. Sequencing results of these five relapse cases showed no mutations in rpoB, folP1 and gyrA genes.

7.9

Yemen

Dr Abdul Rahim Al-Samie presented the data on leprosy surveillance of drug resistance conducted in Yemen in 2010. Yemen is a low burden country for leprosy. The National leprosy elimination programme in Yemen is completely integrated in primary health care (PHC) system and run by Leprosy specialized staff up to second national level and by general staff in the lower levels. Since its inception, the NLEP receives support from WHO, GLRA, YELEP (Local NGO) and MoPH. MDT according to WHO recommendations was introduced in the early 1980s.

The leprosy elimination target was achieved at country level in the year 2000. The leprosy data show a slow but steady decline in new cases, a persistent high rate of Grade 2 disability and satisfactory figures for treatment completion. Dr Al-Samie also presented sample collection facilities in the country. All relapse cases are suspected by the leprosy centres at the second national level and confirmed by medical supervisors from the HQ. The suspected relapse patients are requested to come to the national referral centre. The number of relapses diagnosed yearly fluctuated due to many factors like over diagnosis, mainly due to not following the stringent WHO criteria in the past years. Sometimes underreporting due to non-confirmation of some suspected cases by the MO, especially in areas with security problems. According to relapse data, six relapse cases have been suspected during 2010 by the programme. The samples were collected according to the WHO guidelines and were sent to the Global Health Institute/Switzerland. Only 3 cases were found with sufficient M.leprae DNA. The bacilloscopy results of remaining three samples were negative. The genotyping result for positive three cases showed that they're all from a different genotypes. They belonged to 2-E (East Africa like), 1-D (Asia, Madagascar but also found in South America) and 1-B (this one is rare, only found once in India and two times in French Indies).

8.
8.1

General discussion
Quality control: technology, logistics and reporting

Dr Masanori Matsuoka presented the data about the third round of quality control survey. Six samples were sent to the 17 reference laboratories of the network in nine countries. Among them, 13 labs reported results. Three samples contained DNA at various concentrations from a wild type strain and other three contained a strain that was mutated in rpoB, folP and gyrA. Three laboratories had negative PCR results for some controls with a low concentration whereas only two laboratories did not provide sequencing results. Dr Matsuoka also showed results he obtained (published in Japanese Journal of Infectious Diseases 2011) on the efficiency of the FTA elute card compared to smears in ethanol suspension. Results on 192 samples demonstrated that PCR efficiency is similar with the two methods of skin smear collection.

8.2

M. leprae genomics: impact on transmission, new drug targets and resistance detection

Dr Diana Williams from Louisiana State University presented an overview on M. leprae genomics and the potential benefits for leprosy research. Several strains are being sequenced with representatives of various part of the world. Microarray for transcriptome study is also developed. Genotyping is usually done by VNTR and SNPs analysis. This recently showed the story of the origins of leprosy and its further world-wide dissemination. It also confirms the armadillo to human transmission in the Southern USA. PCR and new RT-PCR protocols are used for the detection of M. leprae DNA and the enumeration of bacterial cells in skin smears. Dr Williams
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described several molecular methods that can be used to detect mutations in the drug targeted genes and showed a new method that is under development (LIPLA system).

8.2

Outcome of management of drugs resistant leprosy cases using second line drugs

Dr Kyaw Kyaw presented two cases of leprosy with rifampicin resistance he had to manage. The first case has a long history of leprosy treatment from 1973 onwards with DDS alone then associated with combination of DDS + clofazimine with or without rifampicin. The actual clinical status was relapse from lepromatous leprosy with BI5+ and a M. leprae strain with mutation in rpoB and folP. The patient was then treated with ofloxacin, clofazimine and minocycline with success. The second case has also a long past history of DDS monotherapy that ended with one year MDT. He relapsed in 2009 with new lesions and BI5+. The strain showed only a rpoB mutation. He was eventually treated with DDS, ofloxacin, minocycline and clofazimine with success.

8.3 Current developments in search for new anti-leprosy drugs

Pr Cambau presented data on new antibiotics that could be useful in the future for the treatment of leprosy. Ofloxacin (or levofloxacin) minocycline and clarithromycin are the usual second line drugs with ethionamide being less active. Moxifloxacin is a new second line drug that has already showed efficacy in leprosy treatment. Promising drugs that showed efficacy in the mouse footpad model are rifapentine, a long acting rifamycin and the new antituberculous drug TMC-207 (Tibotec). All the new antituberculous drugs (nitro-imidazole derivatives for instance) that are currently developed by the Global alliance against TB team should be further tested for leprosy. In conclusion we need to keep testing models for studying the activity of new drugs and drug combinations against M. leprae.

9.

Conclusions and recommendations

The participants acknowledged and appreciated the support provided by various partners and especially LEPRA India - Blue Peter Public Health & Research Centre (BPHRC), Hyderabad, India in hosting this meeting. The results of the ongoing drug resistance surveillance shows that MDT remains an effective treatment In relapsed cases where previous records are not available, the presence of definite new lesions and BI of 2+ and more should be made them included for sentinel surveillance of drug resistance. The existing network of surveillance needs to be expanded to include more sentinel sites and collaborating laboratories.
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The quality control initiative introduced by leprosy research centre, National Institute of Infectious Diseases, Tokyo, Japan, is an important component to drug resistance surveillance and it is to be continued. Initiating studies on efficacy of new antileprosy drugs Referral centres and their collaborating laboratories are encouraged to publish information on the clinical and other scientific aspects of relapse cases in relevant journals. Collaborating laboratories and sentinel sites are encouraged to do additional studies in new MB skin smear positive cases for primary drug Resistance, but these results should be separated from those of the relapsed cases.

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Annex 1

Programme
Day 1: Monday, 22 August 2011 09.00-09.30 hours - Opening session - Welcome address WHO and Blue Peter Public Health and Research Centre - Selection of chairperson and rapporteur - Introduction of participants Coffee/Tea Break Setting the stage Drug Resistance: updates on current situation (Dr Myo Thet Htoon) Discussion Country presentation on relapses: current situation, trends and case management (10 minutes each) - Brazil (Dr Rosa Castalia Soares) - Discussion Lunch break Technical session Continuation of country presentation on relapses - China (Dr Shen Jianping) - Madagascar (Dr Ramarolahy Emerantien Benoit) - Nepal (Dr Garib Das Thakur) - Discussion Being prepared to detect for resistance to second line drugs: new fluroquinolones, clarithromycin, minocycline and TMC207 (Professor Emmanuelle Cambau) - Discussion High throughput routine drug resistance surveillance in leprosy: present and future technologies (Dr Varalakshmi Vissa) - Discussion Coffee/Tea

09:3010:00 hours 10:00- 10:30 hours

10:30 12:30 hours

12:30 14:00 hours 14:00 14:30 hours

14:30 15:00 hours

15:00 15:30 hours

15:30 16:00 hours

Day 2: Tuesday, 23 August 2011 09:00-10:00 hours Country presentations on drug resistance surveillance data: current practices for diagnosis, referral, investigations and results (10 minutes presentation followed by discussion) Brazil (Dr Rosa Castalia Soares) China (Prof Wang Hongsheng) Columbia (Dr Nora Cardona-Castro) India (Dr Rupendra Jahdav, Dr V. Vijaya Laskmi, Dr Ram Das and Dr Krishnamurthy) Coffee/Tea Break Continuation of country presentations (10 minutes presentation followed by discussion) Mali (Dr Mamadou Sidebe and Dr Roch Christian Johnson) Myanmar (Dr Kyaw Kyaw) Nepal (Dr Deanna Hagge and Dr Graeme Clugston) Pakistan (Dr Christine Schmotzer) Philippines (Dr. Irene Mallari) Viet Nam (Dr Tran Hua Khang) 12

10:00-10:30 hours 10:30 12:30 hours

Yemen (Dr Abdul Rahim Al-Samie)

12:30-14:00 hours

Lunch break General discussion

14:00-14:30 hours 14:30-15:00 hours

15:00-15:30 hours

15:30-16:00 hours 16:00- 16:15 hours 16:15-16:45 hours

Quality control: technology, logistics and reporting (Dr M. Matsuoka) - Discussion Current developments in search for new anti-leprosy drugs (Professor Emmanuelle Cambau) - Discussion Outcome of management of drugs resistant cases using second line drugs (Dr Kyaw Kyaw) - Discussion Conclusion and recommendations Closing Coffee/Tea

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Annex 2

List of Participants

National Programme Managers

Brazil

Dr Rosa Castalia Franca Ribeiro Soares Coordinator of the National Programme of Leprosy & Other Elimination Diseases Setor Commercial Sul Quadra 04 Edificio Principal Sala 301-Anexo III, Ministerio da Saude Brasilia-DF Brazil E-mail: rosa.castalia@saude.gov.br (or) castalia46@gmail.com
India

Dr C.M. Agrawal Deputy Director-General (Leprosy) Directorate of Health Services Ministry of Health and Family Welfare Nirman Bhawan, New Delhi 110011 E-mail: ddgl@nb.nic.in
Nepal

Dr Garib Das Thakur Programme Manager National Leprosy Control Division Directorate of Health Services Kathmandu, Nepal E-mail: thakurgd@gmail.com

Focal persons from sentinel sites

Dr Isabela Maria Bernandes Goulart Rua Jose De Paula Dias No.146, Jardim Karaiba-Uberlandia-MG CEP: 38.411-172, Brazil Email: isagoulart@centershop.com.br

Dr Kyaw Kyaw Leprosy Specialist Central Special Skin Clinic Yangon General Hospital
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Yangon, Myanmar E-mail: kyawkyawdr@gmail.com Dr Nguyen Thi Hai Van Secretary National Hospital of Dermatology & Venerelogy (NHDV) Ha Noi, Viet Nam E-mail: khangquoduc@fpt.vn Dr Shen Jianping Deputy Director, Department of Leprosy Control Institute of Dermatology and National Center for Leprosy Control Nanjing, P.R. China 210042 E-mail: SHENJP1@jlonline.com Dr (Ms) Nora Cardona-Castro Institute Columbiano de Medicina Tropical Iniversidad CES Carrera 43 A No. 52 Sur 991 Medellin, Columbia Email: ncardona@CES.EDU.CO Dr Rupendra Jadhav Senior Scientist & Head Stanley Browne Laboratory The Leprosy Mission Community Hospital Nandnagri, Delhi - 110093, India E-mail: rupenjadhav@yahoo.com Dr Sylvestre Marie Roger Tiendrebeogo Directeur de la Lutte Contre la Maladie Burkina Faso E-mail: syltiend@hotmail.com

Dr Ramarolahy Emerantien Benoit Chef de Division de lApprovisionnement et de la Communication Madagascar E-mail: remerantienbenoit@yahoo.fr Dr Mamadou Sidibe Charge du PNLL Direction Nationale de la Sante Ministere de la Sante Mali E-mail: mamadous2001@yahoo.fr Dr Cynthia Sema, MPH Departamento de Vigilancia em Saude Instituto National de Saude Ministerio da Saude Maputo, Mozambique E-mail: cynthiasema@yahoo.com

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Dr Abdul Rahim Al-Samie Director National Leprosy Elimination Programme Skin and Venereal Diseases Hospital Taiz, Republic of Yemen (EMR) E-mail: arahim10@hotmail.com Dr Deanna Hagge Head of Laboratory Anandaban Hospital Kathmandu, Nepal E-mail: deannah@tlmnepal.org & deannahagge@gmail.com Mr Kapil Dev Neupane Anandaban Hospital Kathmandu, Nepal Dr Mahesh Shah Anandaban Hospital Kathmandu, Nepal Dr Graeme Clugston* Superintendent Lalgadh Hospital Kathmandu, Nepal E-mail: clugstong@gmail.com Dr Irene Balenton Mallari Leprosy Research Clinician Leonard Wood Memorial Center for Leprosy Research Cebu, Philippines E-mail: irene_mallari@yahoo.com Dr Padebattu Krishnamurthy Secretary, Damien Foundation India Trust 27 Venugopal Avenue Spur Tank Road Chetpet, Chennai 600 031, India E-mail: damienin@airtelmail.in Dr (Ms) Nguyen Phuc Nhu Hai Deputy Head of Laboratory Department Quyhoa National Leprosy Dermatology Hospital Quynhon City, Binhdinh Province Viet Nam E-mail : nhuha.nguyenphuc@yahoo.com Dr Vijayalakshmi Valluri Group Leader-Immunology & Molecular Biology Division
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LEPRA India - Blue Peter Public Health & Research Center (BPHRC) Near TEC Building, Cherlapally Hyderabad 501 301 Andhra Pradesh, INDIA E-mail: vijayavalluri@rediffmail.com vijayavalluri@hotmail.com

Collaborating Reference Laboratories

Dr Philip Suffys Oswaldo Cruz Foundation Ministry of Health, Av. Brazil 4365 Manguinhos Pavilhao Mourisco S. 105, 21045-900 Rio de Janeiro, Brazil E-mail: psuffys@ioc.fiocruz.br Professor Emmanuelle Cambau National Reference Center for Mycobacteria & Resistance to Anti-tuberculosis Drugs Laboratoire de Bactriologie-Virologie Groupe Hospitalier Lariboisire-Fernand Widal 2 rue Ambroise Par, 75475 Paris cedex 10, France E-mail emmanuelle.cambau@lrb.aphp.fr Dr Masanori Kai Department of Bio-regulation Leprosy Research Centre National Institute of Infectious Diseases 4-2-1 Aoba-cho, Higashimu-rayama-shi Tokyo 189-0002, Japan Email: mkai@nih.go.jp Dr Sang-Nae (Ray) Cho* Department of Microbiology Yonsei University College of Medicine 134 Shinchon-dong, Seoul 120-752 South Korea Email: raycho@yonsei.ac.kr Diana L. Williams, Ph.D. Molecular Biologist Division National Hansen's Disease Programs Laboratory Research Branch Molecular Biology Research Dept. Associate Professor (Adj.) Pathobiological Sciences Dept. School of Veterinary Medicine, Louisiana State University, Rm 3519W Skip Bertman Dr. Baton Rouge, LA, USA 70803 E-mail:dwilliams2@hrsa.gov Professor Stewart Cole* Global Health Institute Ecole Polytechnique Federal de Lausanne Department of Immunology EPFL SV/GHI/UPCOL, Station No: 15 CH-1015 Lausanne, Switzerland Email: stewart.cole@apfl.ch Dr Varalakshmi Vissa Department of Microbiology, Immunology &
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Pathology Colorado State University Fort Collins, Colorado 80523, USA Email: vvissa@colostate.edu Dr Ram Das Department of Microbiology & Molecular Biology National JALMA Institute for Leprosy & Other Mycobacterial Diseases Dr M. Miyazaki Marg, Taj Ganj Agra 282 001, Uttar Pradesh E-mail: ramdas0002@yahoo.com & drrdas_3@yahoo.co.in

Experts
Dr Herman Joseph S. Kawuma (Chairperson, WHO Technical Advisory Group for Leprosy Control) Medical Advisor, German Leprosy Relief Association P.O. Box 3017, Kampala, Uganda E-mail: Kawuma@infocom.co.ug Dr Masanori Matsuoka Chief, Laboratory 1 Department of Bio-regulation Leprosy Research Center National Institute of Infectious Diseases 4-2-1, Aobacho, Higashimurayama Tokyo 189-0002, Japan E-mail: matsuoka@nih.go.jp Dr (Mrs) Khin Saw Aye Head, Immunology Research Division Department of Medical Research Yangon, Myanmar Email: ksadmr@gmail.com *Dr (Ms) Jeanne Bertolli* Associate Chief for Science, Behavioral and Clinical Surveillance Branch Division of HIV/AIDS Prevention Center for Disease Control and Prevention Atlanta, USA E mail: jub7@cdc.gov Dr Paul Saunderson Medical Advisor
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Leonard Wood Memorial Medical Center Cebu, Philippines Email: psaunderson@leprosy.org Professor Patrick J. Brennan* Department of Microbiology, Immunology & Pathology C321 Microbiology Building Colorado State University Fort Collins, Colorado 80523-1682 USA E-mail: patrick.brennan@colostate.edu Professor Wang Hongsheng Associate Professor Institute of Dermatology Chinese Academy of Medical Sciences & Peking Union Medical College National Center for STD and Leprosy Control China CDC Jiangwangmiao Street, Nanjing, Jiangsu 210042, China E-mail: whs33@vip.sina.com & whystyx@hotmail.com Dr Vijaykumar Pannikar (Former Team Leader, WHO Global Leprosy Programme) No 204, S.S. Paradise Doda Banaswadi, Outer Ring Road, Bangalore, Karnataka State 560 043 E-mail : pannikarv@gmail.com Professor Jacques H. Grosset* Center for Tuberculosis Research Johns Hopkins University School of Medicine CRB II, Room 105, 1550 Orleans Street Baltimore, Maryland 21231-1001 USA E-mail: jgrosse4@jhmi.edu & jacques_grosset@yahoo.com

PARTNERS
LEPRA

Dr J. Subbanna Director, LEPRA India Blue Peter Public Health & Research Center Near TEC Building,Cherlapally Hyderabad 501 301 Andhra Pradesh, INDIA Professor Diana Lockwood Senior Lecturer London School of Hygiene & Tropical
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Medicine Keppel Street London WC1E 7HT United Kingdom E-mail:diana.lockwood@lshtm.ac.uk Dr (Lt. Gen.) V.D. Tiwari Vice Chairman, LEPRA India and RAC-Chairman LEPRA India - Blue Peter Public Health & Research Center Near TEC Building, Cherlapally Hyderabad 501 301 Andhra Pradesh Dr P.V. Ranganadha Rao Chief Executive, LEPRA India Blue Peter Public Health & Research Centre (BPHRC) Near TEC Building, Cherlapally Hyderabad 501 301 Andhra Pradesh
Raoul Follereau Foundation

Dr C. Johnson Fondation Raoul Follereau BP: 25 Abomey-Calavi Bnin 31, Rue de Danzing, 75015 Paris, France E-mail: rochjohnson@yahoo.fr Dr B. Cauchoix Fondation Raoul Follereau S/C Direction des projets sant 31 Rue de Dantzig 75015 Paris, France E-mail: cauchoixbertrand4@gmail.com; drcauchoix@raoul-follereau.org

WHO Secretariat
Dr Myo Thet Htoon Team Leader Global Leprosy Programme WHO-SEARO E-mail: htoonm@searo.who.int

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Dr Sumana Barua Regional Adviser Leprosy WHO-SEARO E-mail: baruas@searo.who.int Dr Landy Bide Regional Adviser Leprosy WHO-AFRO Brazaville E-mail:bidel@whoafr.org Dr Hany Ziady Medical Officer/CTD and Focal Point for Leprosy WHO-EMRO E-mail: ziadyh@emro.who.int Mr Vishwanathan K.R. Administrative Assistant WHO-SEARO E-mail: viswanathank@searo.who.int
*Invited but unable to attend

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Annex 3

Reference laboratories collaborating with the WHO Global Leprosy Programme for sentinel surveillance of rifampicin resistance
1. Department of Microbiology Yonsei University College of Medicine 134 Shinchon-dong, Seoul 120-752, South Korea Tel. No.: +822-2228-1819; Fax No.: +822-392-9310 Email: raycho@yonsei.ac.kr Leprosy Research Centre National Institute of Infectious Diseases 4-2-1 Aoba-cho, Higashimu-rayama-shi Tokyo 189-0002, Japan Tel. No.: 81-42-391-8211 Fax No.: 81-42-394-9092 Email: mkai@nih.go.jp; Central JALMA Institute for Leprosy and Other Mycobacterial Diseases Dr M. Miyazaki Marg, Taj Ganj Agra 282 001, India Tel. No. : +91-562-2331751 Fax No. : +91-562-2331755 Email: vishwamohan_katoch@yahoo.co.in Global Health Institute Ecole Polytechnique Federal de Lausanne EPFL SV/GHI/UPCOL, Station No.19, CH-1015 Lausanne, Switzerland Tel. No. +41 21 693 1851 Fax No. +41 21 693 1790 Email: stewart.cole@apfl.ch Oswaldo Cruz Foundation Ministry of Health, Av. Brazil 4365 Manguinhos Pavilhao Mourisco S. 105 21045-900 Rio de Janeiro, Brazil Tel. 55 21 2590 4712 Fax: 55 21 2590 9741 Email: euzenir@uol.co.br Division of National Hansens Disease Programme Laboratory Research Branch Louisiana State University, School of Veterinary Medicine
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2.

3.

4.

5.

6.

Room 3517W, Skip Bertman Drive, Baton Rouge, LA 70803 Tel: 225-578-9836 Fax: 225-578-9856 Email: tgillis@lsu.edu 7. National Reference Center for Mycobacteria and resistance to anti-tuberculosis drugs Department of Bacteriology and Hygiene Faculty of Medicine 91 Boulevard de Hospital 75634 Paris Cedex 13, France Email: Emmanuelle.cambau@lrb.aphp.fr Immunology and Molecular Biology Division Blue Peter Research Center, Near TEC Building Cherlapally, Hyderabad 501 301 Andhra Pradesh, India Tel: 40 272 64547 Email: vijayavalluri@rediffmail.com Stanley Browne Laboratory The Leprosy Mission Community Hospital Nandnagri, Delhi 110093, India Tel: 91 11 225 94295 Email: rupenjadhav@yahoo.com Department of Microbiology, Immunology and Pathology Colorado State University Fort Collins CO 80523, USA Tel: 970 491 0751/4139/6390 Fax: 970 491 1815 Email: weili@colostate.edu

8.

9.

10.

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